Acute myeloid leukemia (AML) is a heterogeneous disorder that includes many entities with diverse genetic abnormalities and clinical features1. The pathogenesis is known for relatively few types of leukemia2. Patients with intermediate and poor risk cytogenetics represent the majority of AML; chemotherapy based regimens fail to cure most of these patients and stem cell transplantation is frequently the treatment choice3-4. Since allogeneic stem cell transplantation is not an option for many patients with high risk leukemia, there is a critical need to improve our understanding of the biology of these leukemias and to develop improved therapies.
Systematic high-throughput analysis of mRNA expression levels in AML has described new molecular subgroups of AML; some of these have been suggested to predict outcome5-6. Despite this progress, focusing on known genes will likely not suffice to uncover the molecular puzzle of AML. The integration of a whole genome approach including non-coding RNAs may lead to an improved understanding of AML biology.
MicroRNAs (miRNAs) are non-coding RNAs of 19-25 nucleotides in length that regulate gene expression by inducing translational inhibition or cleavage of their target mRNA through base pairing to partially or fully complementary sites7. The miRNAs are involved in critical biological processes, including development, cell differentiation, apoptosis and proliferation8. Recently, miRNA expression has been linked to hematopoiesis and cancer9-11. Calin et al. have shown deletions and down-regulation of miR-15a and miR-16-1 in chronic lymphocytic leukemia12. Several groups have reported changes in miRNA expression in large cell lymphoma13 and pediatric Burkitt lymphoma14. More recently, it has been shown that over-expression of miR-155 in B cells of transgenic mice results in polyclonal B cell proliferation and B cell neoplasia15. These observations indicate that miRNAs are involved in the initiation and progression of human cancer.
As disclosed herein, miRNA microarrays are used to profile a large set of AML patients with predominately intermediate and poor prognosis to investigate the association of miRNA profiles with cytogenetic groups and clinical features.
Identification of microRNAs that are differentially-expressed in acute myeloid leukemia cancer cells would aid in diagnosing, prognosticating and treating leukemia. Furthermore, the identification of putative targets of these miRNAs would help to unravel their pathogenic role. In one broad aspect, there is provided herein provides novel methods and compositions for the diagnosis, prognosis and treatment of acute myeloid leukemia.